Here we present our results that show highly regio- and chemoselective cysteine perfluoroarylation under mild conditions for the synthesis of abiotic biopolymers (JACS 135:5946, 2013; ACIE 52:14001, 2013; OBC12:566, 2014; OL 16:3652, 2014) Cysteine perfluoroarylation is compatible with unprotected peptides. Reactions can be monitored with 19F NMR spectroscopy and LCMS in situ. 1,4- and 1,10- substitution patterns (para) were exclusively observed for reactions with hexafluorobenzene and decafluorobiphenyl respectively under the developed conditions.
Improved properties of bioactive peptides were observed when stapled in an i, i +4 arrangement with hexafluorobenzene or decafluorobiphenyl. Model studies were undertaken with stapled peptides that target the C-terminal domain of an HIV-1 capsid assembly polyprotein. Variants penetrate cells at levels comparable to hydrocarbon-linked peptide reported by Cowburn et al. Stapling is required for cell penetration; experiments with non-crosslinked variants that contained pentafluorobenzene or nonafluoro-biphenyl displayed no cellular uptake. Following this work, we discovered an enzyme-catalyzed version of the cysteine arylation capable of operating in water, as well as a more comprehensive study aimed at optimizing arylation chemistry for macrocyclization. Lastly, we will discuss the use of arylation chemistry for the site-specific modification of antibodies by use of a novel mini self-labeling protein.